Sleep-disordered breathing, including sleep apnea (SA), is characterized by cyclical interruption of breathing during sleep, often caused by intermittent airway obstruction. SA is emerging as a highly prevalent cause of death and disability. In addition to hypertension and cardiac diseases, SA is an independent risk factor for stroke, and increases its incidence by 2-4 folds. The development of mechanism-based therapies has been hampered by the lack of insight into how SA increases the risk of cerebrovascular insufficiency and stroke. Although the pathophysiology of SA is likely to be multifactorial, chronic intermittent hypoxia (CIH) caused by the apneic episodes is considered a critical factor in the cardiovascular complications. In the systemic circulation, CIH, like SA, alters vascular function, but little is known about the impact of these alterations on the regulation of organ blood flow and on end-organ damage, particularly in brain. Considering the brain's unique susceptibility to vascular insufficiency, disruption of the regulation of the cerebral blood supply by CIH could compromise the delivery of adequate blood flow to the tissue and promote ischemic injury. The present proposal will test the central hypothesis that CIH exerts its deleterious effect on the brain by altering key cerebrovascular homeostatic mechanisms, reducing vascular reserves and increasing the vulnerability of the brain to ischemia. In particular, we will test the following specific hypotheses in four aims: (1) CIH disrupts the delivery of blood to the brain by altering vital regulatory mechanisms that assure adequate cerebral perfusion, such as functional hyperemia and cerebrovascular autoregulation; (2) CIH exerts its deleterious cerebrovascular effects by inducing vascular oxidative stress through the superoxide producing enzyme NADPH oxidase; (3) Upregulation of endothelin-1 in cerebral blood vessels, via ETA receptors, plays a major role in the neurovascular dysfunction; (4) The detrimental cerebrovascular effects of CIH deplete cerebrovascular reserves, aggravate the brain ischemia induced by middle cerebral artery occlusion, and increase the resulting tissue damage. These hypotheses will be tested using a mouse model of CIH and well-established approaches to examine cerebrovascular regulation and ischemic brain injury. The results of the proposed studies will provide new insights that may advance our understanding of the cerebrovascular complications of SA. PUBLIC HEALTH RELEVANCE: Disorders of breathing during sleep, including sleep apnea, have emerged as independent risk factors for stroke, especially silent strokes. The proposed studies will advance our understanding of the pathophysiological substrates underlying the increased susceptibility to ischemic injury in sleep apnea. Ultimately, the results of the proposed studies may suggest novel mechanism-based approaches to prevent or treat the deleterious effects of this highly prevalent condition.